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Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Non

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Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Non DMD Fast Forward. Published on December 23, 2019 as DOI: 10.1124/dmd.119.089680 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 89680 1 Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Non- Genetic Regulators Lucy Her and Hao-Jie Zhu Department of Clinical Pharmacy (L.H. and H.-J.Z.), University of Michigan, Ann Arbor, Michigan Downloaded from dmd.aspetjournals.org at ASPET Journals on October 1, 2021 DMD Fast Forward. Published on December 23, 2019 as DOI: 10.1124/dmd.119.089680 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 89680 2 Running title: Carboxylesterase 1 and Precision Pharmacotherapy Corresponding author: Hao-Jie Zhu Ph.D. Department of Clinical Pharmacy University of Michigan College of Pharmacy 428 Church Street, Room 4565 NUB Ann Arbor, MI 48109-1065 Tel: 734-763-8449, E-mail: [email protected] Number of text pages: 25 Number of tables: 4 Downloaded from Number of figures: 5 Number of references: 102 Number of words in Abstract: 223 Number of words in Introduction: 166 Number of words in Discussion: 287 dmd.aspetjournals.org Keywords: Carboxylesterase 1, pharmacogenetics, precision pharmacotherapy List of Abbreviations: at ASPET Journals on October 1, 2021 ADHD attention deficit hyperactivity disorder API active pharmaceutical ingredient AT I angiotensin i AT II angiotensin ii AUC area under the curve BCS biopharmaceutics classification system CES1 carboxylesterase 1 CES2 carboxylesterase 2 CI confidence interval Cmax maximum plasma concentration CNVs copy number variations Clinical Pharmacogenetics Implementation CPIC Consortium CYPs cytochrome p450 DL-EPH dl-ethylphenidate DMEs drug-metabolizing enzymes FDA Food and Drug Administration GWAS genome-wide association study INH isoniazid LD loading dose LOF loss-of-function DMD Fast Forward. Published on December 23, 2019 as DOI: 10.1124/dmd.119.089680 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 89680 3 MAF minor allele frequency MD maintenance dose OR odds ratio PCI percutaneous coronary intervention PD pharmacodynamics PK pharmacokinetics PNPA p-nitrophenyl acetate PTM post-transcriptional modification SNPs single-nucleotide polymorphisms T2DM Type 2 Diabetes Mellitus Downloaded from dmd.aspetjournals.org at ASPET Journals on October 1, 2021 DMD Fast Forward. Published on December 23, 2019 as DOI: 10.1124/dmd.119.089680 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 89680 4 Abstract Carboxylesterase 1 (CES1) is the most abundant drug-metabolizing enzyme in human livers, comprising approximately 1% of the entire liver proteome. CES1 is responsible for 80-95% of total hydrolytic activity in the liver and plays a crucial role in the metabolism of a wide range of drugs (especially ester-prodrugs), pesticides, environmental pollutants, and endogenous compounds. Expression and activity of CES1 vary markedly among individuals, which is a major contributing factor to interindividual variability in the Downloaded from pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by CES1. Both genetic and non-genetic factors contribute to CES1 variability. Here, we discuss dmd.aspetjournals.org genetic polymorphisms, including single-nucleotide polymorphisms (SNPs) and copy number variants, and non-genetic contributors, such as developmental status, genders, and drug-drug interactions, that could influence CES1 functionality and the PK and PD at ASPET Journals on October 1, 2021 of CES1 substrates. Currently, the loss-of-function SNP G143E (rs71647871) is the only clinically significant CES1 variant identified to date, and alcohol is the only potent CES1 inhibitor that could alter the therapeutic outcomes of CES1 substrate medications. However, G143E and alcohol can only explain a small portion of the interindividual variability in the CES1 function. A better understanding of the regulation of CES1 expression and activity and identification of biomarkers for CES1 function in vivo could lead to the development of a precision pharmacotherapy strategy to improve the efficacy and safety of many CES1 substrate drugs. DMD Fast Forward. Published on December 23, 2019 as DOI: 10.1124/dmd.119.089680 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 89680 5 Significance Statement Carboxylesterase 1 (CES1) is a major phase I drug-metabolizing enzyme responsible for 80-95% of total hydrolytic activity in human livers. CES1 plays a crucial role in metabolizing a wide range of drugs, pesticides, environmental pollutants, and endogenous compounds. The clinical relevance of CES1 has been well demonstrated in various clinical trials with methylphenidate, oseltamivir, and clopidogrel. Here, we discuss genetic polymorphisms and non-genetic contributors that influence CES1 Downloaded from functionality and the PK and PD of drugs metabolized by CES1. dmd.aspetjournals.org at ASPET Journals on October 1, 2021 DMD Fast Forward. Published on December 23, 2019 as DOI: 10.1124/dmd.119.089680 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 89680 6 1. Introduction Carboxylesterase 1 (CES1) is a phase I drug-metabolizing enzyme (DME) responsible for 80-95% of total hydrolytic activity in the liver (Imai et al., 2006); it metabolizes a wide range of drugs, pesticides, environmental pollutants, and endogenous compounds, including lipid esters (Table 1). CES1-mediated metabolism can lead to the biotransformation of a pharmacologically active drug into its inactive metabolite, as exemplified by methylphenidate hydrolysis in the liver. CES1 also plays Downloaded from an important role in activating prodrugs since most ester-containing prodrugs are exclusively dependent on CES1 for their activation. The clinical relevance of CES1 has dmd.aspetjournals.org been well demonstrated in various clinical trials with oseltamivir, methylphenidate, and clopidogrel (Zhu et al., 2008; Tarkiainen et al., 2012; Lewis et al., 2013; Jiang et al., 2016). Recent studies have also revealed that CES1 acts as a cholesteryl ester at ASPET Journals on October 1, 2021 hydrolase in lipid metabolism in human macrophages and hepatocytes, and suggest CES1 as a potential drug target for the treatment of metabolic diseases, such as diabetes and atherosclerosis (Dolinsky et al., 2004; Zhao et al., 2007; Ghosh et al., 2010; Ross et al., 2010; Lian et al., 2018b). 2. Importance of CES1 in drug metabolism CES1 plays an important role in metabolizing many clinically significant medications, especially the ester-prodrugs (Table 1). A prodrug refers to an inactive drug molecule that needs to be enzymatically biotransformed in vivo to its active metabolite to produce its intended pharmacological effect (Rautio et al., 2008). Prodrug design offers an attractive method to overcome the issue of low bioavailability for Biopharmaceutics Classifications System (BCS) class III drug molecules. Drug DMD Fast Forward. Published on December 23, 2019 as DOI: 10.1124/dmd.119.089680 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 89680 7 molecules can be categorized into four BCS classes based on permeability and solubility, and a BCS class III substance is a hydrophilic compound with low permeability and high solubility (Shah and Amidon, 2014). In particular, hydrophilic compounds with – OH or –COOH functional groups usually have difficulty being absorbed into the body, and drug developers often mask these functional groups using an ester-prodrug design. The prodrug market has been growing: 20% of drugs approved in 2015 were prodrugs, compared to ~6% of all currently approved drugs (Rautio et al., 2017). Downloaded from Two major assumptions behind the ester-prodrug design are that prodrugs are rapidly activated via unspecific esterases in the body, and that the interindividual dmd.aspetjournals.org variability in activating a prodrug is clinically insignificant. These incorrect assumptions may have stemmed from the fact that many hydrolytic enzymes exist in the body, such as CES1, CES2, acetylcholinesterase, butyrylcholinesterase, paraoxonases, and at ASPET Journals on October 1, 2021 arylesterase. However, these hydrolases differ in their tissue-specific expression, cellular localization, and most importantly, substrate selectivity (Fukami and Yokoi, 2012). In humans, CES1 is highly abundant in the liver and expressed to a less extent in the lung and brain; CES1 expression is considered negligible in the human intestine, kidney, and plasma. CES1 is substrate-selective towards carboxyl esters with a large ethyl group and a small alcohol group. In comparison, CES2, another major carboxylesterase in humans, is highly expressed in the intestine, kidney, and liver, and is more efficient at metabolizing compounds with a small ethyl group and a large alcohol group (Jewell et al., 2007). Numerous in vivo and in vitro studies have demonstrated the specificity of CES1, and many CES1 substrates cannot be metabolized by other esterases (Table 3). DMD Fast Forward. Published on December 23, 2019 as DOI: 10.1124/dmd.119.089680 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 89680 8 CES1 expression and activity vary significantly among individuals (Wang et al., 2016a);
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